To investigate the pathogenetic mechanisms of tubule nephrotoxicity of low molecular weight proteins (LMWP), proximal tubules (PT) of rats were perfused in vivo with artificial tubule fluid (ATF) containing one of five LMWPs: three human Bence Jones proteins (BJP), f-lactoglobulin (BLG), and rabbit myoglobin (MYG). Volume (J4), chloride (Jce) and glucose (JG) fluxes in these perfused PTs were compared with those determined using ATF alone. In separate experiments, perfused nephrons were examined with electron and immunoelectron microscopy. After exposure to IHJP1 or BLG, Jv, Jc0, and JG were less (P < 0.05) than corresponding control fluxes. Cell damage of these perfused PTs, along with cellular debris in the distal tubules, was prominent. The PT lysosomes often appeared atypical and contained crystals. In contrast, perfusion with BJP2, BJP3, or MYG did not alter Jv, Jcj, or JG. These findings were corroborated by the normal ultrastructure of these PTs despite immunohistochemical evidence of endocytosis of the BJPs. Isoelectric point, molecular form, and isotype were not factors associated with PT damage. In addition, proteins with pI < 7.4 precipitated in the distal nephron, forming acellular casts.